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HLA and other susceptibility genes in rheumatoid arthritis

Sebastien Viatte, MD, PhD
Section Editor
Peter H Schur, MD
Deputy Editor
Paul L Romain, MD


The association of a particular human leukocyte antigen (HLA) with rheumatoid arthritis (RA) was first noted in the late 1970s, when the frequency of individuals with the HLA-Dw4 serotype was found to be increased among RA patients compared with healthy controls [1,2]. This particular serotype represented a set of alleles at the HLA-DRB1 gene locus. Subsequently, hundreds of studies have examined and expanded that association in order to better elucidate the genetic underpinnings of RA. Both linkage and association studies of the HLA-DRB1 gene have consistently confirmed that it is the major genetic susceptibility locus for RA. As such, it provides an important clue to RA pathogenesis.

Since about 2005, discoveries using high-throughput genotyping in large sample collections have identified over 100 additional genetic loci outside of the HLA locus that play a relatively modest role in RA risk but implicate critical pathways in its pathogenesis [3]. Further investigation has also begun to fine-map these RA loci, including the DRB1 gene. However, the issue of clinical utility of genotyping in patients with RA remains unresolved.

The role of HLA and other susceptibility genes in RA will be addressed in this topic review. The epidemiology of, risk factors for, causes of, and pathogenesis of RA, as well as an overview of HLA genes and their nomenclature, are discussed separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Pathogenesis of rheumatoid arthritis" and "Human leukocyte antigens (HLA): A roadmap".)


HLA alleles and susceptibility to rheumatoid arthritis — Both linkage and association studies have established that the human leukocyte antigen (HLA)-DRB1 gene is the major genetic susceptibility locus for rheumatoid arthritis (RA). Interpretation of early studies of HLA associations in RA has been complicated by evolving changes in nomenclature and methods of HLA typing [4]. Originally, HLA typing was achieved with immunological reagents. The methods subsequently used for HLA typing in RA have involved amplification by the polymerase chain reaction of the highly polymorphic second exon of the HLA-DRB1 gene, followed by probing with a DNA sequence-specific oligonucleotide probe. Direct nucleotide sequencing is an alternative method of genotyping. A newer technique for HLA typing has since been developed for further analysis of individuals with available dense single nucleotide polymorphism (SNP) genotyping data over the HLA region [5]. (See "Human leukocyte antigens (HLA): A roadmap" and 'Individual amino acid sites and rheumatoid arthritis risk' below.)

Individual alleles and the shared epitope — Two alleles, DRB1*04:01 and DRB1*04:04, primarily account for the originally observed serological association of DR4 with RA in Caucasians. In addition, serological associations with DRB1*01 and DRB1*10 alleles have been noted in many Caucasian RA patients who are negative for DRB1*04 alleles. (See 'Associations in different ethnic populations' below.)

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Literature review current through: Nov 2017. | This topic last updated: Oct 05, 2017.
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